Sintesis Estereoselectiva de 2'-desoxi-aciclo-, e isonucleósidos

Identifier:  TDX:761

Handle: https://hdl.handle.net/20.500.11797/TDX761

Authors:  Viso Acosta, Antonio

Abstract:
In the present PhD-thesis doctoral titled 'Stereoselective synthesis of 2'-desoxi-, acyclo, and isonucleosides' new methods have been developed to obtain nucleosides. The work has been divided in three sections sumarized below: <br/> <br/>Firstly 2-deoxy-2-sulfenyl-arabino-&#61537;-nucleosides and 2-deoxy-ribo-&#61538;-nucleosides were obtained with excellent stereoselectivity from 1-thio-ribo- and 1-thio-arabino-glycosides in a one pot reaction under Mitsunobu conditions. The stereoselectivity depends on the substituent bonded to the sulfur and on the reaction conditions, particulary the solvent. From the results obtained it can be concluded that the reaction intermediate is an oxonium cation and not the thiiranium cation. DFT calculations for determining the geometry of reaction intermediates in glycosilation reactions support an average structure between oxonium and thiiranium cation for tetrahydrofurane and tetrahydrothiofene derivatives. This is the result of a weak interaction between the heteroatom and C-1, which helps to stabilize the cation. Electron donor substituents bonded to external heteroatom (R in SR and SeR) or electronwithdrawing groups bonded to O-5, produce an important change in the geometry: the reaction intermediate becomes more like an episulfonium, episelenonium or iodonium cation. The structure of tetrahydropyrrole derivatives is iminium-like. This fact agrees with the electrondonor properties of nitrogen, which are better than those of oxygen and sulfur. When strong electronwithdrawing groups are bound to the endocyclic heteroatom, or they do not have an electron pair, their structures are episulfonium, episelenonium- and iodonium-like cations. Obviously, this is also the case for the carbocyclic derivatives.<br/><br/>Next, enantiopure 2,5-dihydrofuran derivatives were prepared from (S)-glycidol by a new reaction sequence involving epoxide opening with a vinylcuprate, selenium induced cyclization to give exclusively the 5-endo product, and selective elimination of selenoxide. Unsaturated acyclonucleosides of Z configuration were obtained in a straightforward way by treating 2.5-dihydrofuran with iodotrimethysilane in the presence of silylated purinic or pyrimidinic bases. The synthetic procedure include two consecutive reactions, dihydrofuran ring-opening by trimethylsilyl iodide and subsequently substitution of iodine by the nucleic base.<br/> <br/>New strategies have been explored to obtain isonucleosides: <br/>In first place have been studied the iodine and selenium-promoted thiocyclization, obtaining the following conclusions: <br/>-the iodine and selenocyclization of 1-thio-4-penten-2,3-dioles are totally regio and chemioselective, not being observed in any cyclization by the alcohol.<br/>-the 2-thio-4-penten-1-oles, react always for via 5-endo, however the cyclization of the 1-thio-4-penten-2-oles depend on the electrophile.The product 5-exo is obtained in the seleno promoted thiocyclizations and the product 6-endo in the iodine promoted thiocyclizations.<br/>-we have synthesized 5-deoxi-5-phenyl-selenenyl-thio-nucleosides for the reaction of the 5-[(phenylselenenyl)methyl]tetrahydrothiofen-3-oles with adenine under Mitsunobu conditions. <br/> <br/>Finally, the synthesis of 3-methylen-dideoxi-isonucleosides has been explored. The intramolecular cyclization via radical of methylene-aldehydes, induced by SmI2, leads for 3-methylene-1,4-anhydro-pentenoles to low yields and stereoselectivities. These compounds are precursors for 3-methylene-dideoxy-isonucleosides.